Sepsis is a common occurrence during long term transhepatic biliary drainage. Most of these episodes are attributed to cholangitis, are relatively minor and can be managed nonoperatively. During a 42 month period, nine patients who had sepsis develop after biliary drainage were found to have acute cholecystitis, a complication not previously noted after this procedure. Seven of the nine patients had an underlying malignant lesion, and three of these patients had undergone percutaneous biliary drainage for palliation of unresectable or metastatic tumor. Eight of the nine patients underwent cholecystectomy whereas percutaneous cholecystostomy was used in one patient with an unresectable cholangiocarcinoma. Operative and pathologic evidence of acute cholecystitis was present in all, but only two patients had gallstones. Seven patients survived the surgical procedure and were discharged at an average of 11.7 days postoperatively. Based on this series, we propose that acute cholecystitis should be considered as a source of sepsis in patients undergoing biliary drainage who do not respond to antibiotics and catheter manipulations. Moreover, cholecystectomy should be performed at the time of laparotomy, if prolonged transhepatic drainage is planned for unresectable malignant conditions.